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Summary (continued)

Discussion

In conclusion, based on the meta-analyses of the incidences of total deaths and of ventricular tachycardia and ventricular fibrillation in ischemia- and/or reperfusion-induced arrhythmias, fish oil supplementation has anti-arrhythmic effects in the rat model when compared to omega-6-fatty acid supplementation. Fish oil supplementation in rats showed significant protective effects for ischemia- and reperfusion-induced arrhythmias by reducing the incidence of ventricular tachycardia and fibrillation. The anti-arrhythmic effects seemed stronger in ischemia-induced arrhythmias than in reperfusion-induced arrhythmias. No beneficial effects on ischemia- and/or reperfusion-induced arrhythmias in the rat model were found for ALA supplementation compared to omega-6-fatty acid supplementation. Results were consistent in the two studies that directly compared the anti-arrhythmic effects of ALA oils to fish oils. The incidence of total deaths, ventricular tachycardia, and ventricular fibrillation were lower in rats fed fish oil compared to rats fed soybean or linseed oils.

In monkey models, fish oil supplementations were found to prevent deaths in ischemia- and isoproterenol-induced arrhythmias in one study. In addition, three studies examined ventricular fibrillation threshold and the incidence of ventricular fibrillation in induced arrhythmias. No anti-arrhythmic effects were seen in normal and ischemic conditions. There was a non-significant reduction in the incidence of ventricular fibrillation, and an increase in ventricular fibrillation threshold, in isoproterenol-induced arrhythmias among monkeys fed fish oils compared to monkeys fed sunflower seed oil. Five studies showed consistent protective effects on ischemia- and/or reperfusion-induced arrhythmias in rats, rabbits, or pigs fed fish oils compared to rats fed saturated fatty acids, although again the results were not statistically significant for most comparisons.

In comparison to omega-6, monounsaturated, or saturated fatty acids, or no treatment controls across various species (rats, monkeys, dogs, rabbits, and pigs), we conclude that fish oil supplementation might have anti-arrhythmic effects when compared to omega-6 or monounsaturated fatty acid supplementation. The anti-arrhythmic effects were apparent when animals fed fish oil were compared with those fed saturated fatty acids or with no treatment controls. In most of the studies that showed non-significant reduction in the incidence of death, ventricular tachycardia, and ventricular fibrillation, the lack of significance was likely due to lack of statistical power. The mechanisms of the observed anti-arrhythmic effects of albumin-bound ALA, EPA, and DHA or fish oil emulsion are still unknown. Therefore, we conclude that the arrhythmic effects for albumin-bound ALA, EPA, DHA, and fish oil emulsion are unknown.

In studies using whole isolated organ and cell culture studies and whole animal isolated organs and cells, the question regarding plausible biochemical or physiological mechanisms to explain the potential antiarrhythmogenic effects of omega-3 fatty acids cannot be answered definitively at this time due to the limited number of studies for each outcome and the conflicting results obtained. Some trends were observed among the contractility and ion pumps and ion movement parameters, but these trends need further validation.

Limitations and Recommendations

Synthesizing data regarding the effects of omega-3 fatty acids on arrhythmogenic mechanisms was complicated by a number of issues. Several of these are discussed below and recommendations for future studies are highlighted.

In human clinical trials, randomization, allocation concealment, blinding of investigators and subjects, and adequate sample size are recognized as key factors that might affect the quality of a study and the reliability of study results. Many of these factors were not observed in the 26 whole-animal studies reviewed. For example, only three studies explicitly reported the randomization to treatment, and no study reported blinded analyses. Animal characteristics and housing conditions were described in most studies; however, cross-referencing to prior papers was common. Contemporary controls were used in all but monkey and infusion studies. Exclusion criteria were rarely used.

In addition, while 26 whole-animal studies were identified, approximately 70 percent of studies included in the meta-analyses are from the same group of collaborating researchers, which to some degree accounts for the standardization of arrhythmic outcome measures. The results reported from one laboratory should be independently verified by another. More research from various laboratories on potential mechanisms for the effects of omega-3 fatty acids on arrhythmia is needed.

With respect to study design, standardized measures are needed, especially for isolated organ and cell culture studies. Research would be more interpretable if core sets of standardized measures that produce the highest information yield were agreed upon. We grouped outcomes reported in the various studies into five major categories to aid in the summary of results. However, we found wide variation in reports of the same outcome due to different experimental methodologies.

Tissues or cells from various species of animals, including mice, rats, guinea pigs, ferrets, dogs, pigs, and cats, were used to examine the effect of omega-3 fatty acids on arrhythmogenic mechanisms. It appears, however, that the results are not always applicable across species, all cardiac cell types used (atrial, ventricular, etc.), and all development stages (neonatal, adult). It would, therefore, be useful to reach a consensus on the animal model or models whose basic cardiac physiology, biochemistry, and fatty acid metabolism are as similar as possible to human cardiac tissue, and then for the various research groups to use these models to conduct their experiments.

We found that the concentrations of omega-3 fatty acids used in the isolated organ and cell culture studies were markedly different (1 µM to 214 µM). The results obtained at concentrations greater than 20 µM are questionable due to non-specific effects such as detergent effects on ion channels. Thus there is a need to develop standard preparations of omega-3 fatty acids (e.g., both as free fatty acid and triacylglycerol) that would be available from the NIH or other suppliers to all researchers with a valid protocol. Additionally, a consensus needs to be reached on dosage.

While most studies reported results compared to a control, it might be more relevant to use an omega-6 fatty acid or a monounsaturated fatty acid as the comparison group. Additionally, only three studies evaluated the effect of one omega-3 fatty acid compared to another omega-3 fatty acid. This area needs further research.

Classifying studies by experimental condition and agent used is problematic. It might be appropriate to convene an expert panel to evaluate and standardize available methodologies (ischemic models versus arrhythmogenic models) that are more relevant to the human situation so that the results are comparable across studies and are more applicable or generalizable to humans.

Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Tufts-New England Medical Center Evidence-based Practice Center, Boston, MA, under Contract No. 290-02-0022. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 92, Effects of Omega-3 Fatty Acids on Arrhythmogenic Mechanisms in Animal and Isolated Organ/Cell Culture Studies.